Platelet anti-aggregative- and calcium antagonistic -1,4-benzothiazin-3-one derivatives, compositions, and methods of use therefor

ABSTRACT

This invention relates to benzothiazine derivatives represented by the formula [I] and salts thereof, which are useful for treatment of cardiovascular diseases. ##STR1##

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel benzothiazine derivatives of the formula[I] and salts thereof, ##STR2## wherein R¹ is selected from the groupconsisting of hydrogen, hydroxy, (C₁ -C₆)alkoxy, (C₁ -C₆)alkanoyloxy,(C₁ -C₆)alkoxycarbonyloxy, tetrahydropyranyloxy, amino, (C₁-C₆)alkylamino and ##STR3## R² is selected from the group consisting ofhydrogen, (C₁ -C₆)alkyl, halogen, nitro, hydroxy, amino, (C₁ -C₆)alkoxy,(C₁ -C₆)alkanoyloxy, (C₁ -C₆)alkylamino and (C₁ -C₆)alkoxycarbonyloxy;

R³ is hydrogen, (C₁ -C₆)alkyl or ##STR4## R⁴ and R⁵ are same ordifferent and are selected from the group consisting of hydroxy,halogen, methoxy, ##STR5## R⁶ and R⁷ are same or different and areselected from the group consisting of hydrogen, (C₁ -C₆)alkyl, (C₄-C₇)cycloalkyl and phenyl-(C₁ -C₆) alkyl, and said phenyl nucleus can besubstituted by hydroxy, (C₁ -C₆)alkyl or (C₁ -C₆)alkoxy;

R⁸ is selected from the group consisting of hydrogen, (C₁ -C₆)alkyl, (C₁-C₆)alkanoyl, (C₁ -C₆)alkoxycarbonyl, carboxy, phenyl, phenylcarbonyl,phenyl-(C₁ -C₆)alkyl, phenyl-(C₁ -C₆)alkanoyl, and phenylcarbonyl-(C₁-C₆)alkyl, and said alkyl and alkanoyl groups can be substituted byhydroxy, (C₁ -C₆)alkoxy, carboxy, (C₁ -C₆)alkoxycarbonyl, halogen,amino, (C₁ -C₆)alkylamino or tetrahydropyranyloxy, and said phenylnucleus can be substituted by (C₁ -C₆)alkyl, hydroxy, (C₁ -C₆)alkoxy,(C₁ -C₆)alkanoyl, (C₁ -C₆)alkoxycarbonyl, halogen, amino or (C₁-C₆)alkylamino;

A, B and Z are same or different and are (C₁ -C₆)alkylene; and

m and n each is 0 or 1,

when R³ is hydrogen or n is 0, R¹ represents ##STR6## or hydroxy.

The compounds of this invention are novel benzothiazine derivatives.Main structure of the compounds is 3-oxo-1,4-benzothiazine wherein the2-position of benzothiazine ring is substituted by substituted phenylgroup.

2-Phenyl-3-oxo-1,4-benzothiazine derivatives are reported by J. Krapcho(U.S. Pat. No. 3,166,554 and Brit. Patent No. 960,612), Stearns et al.(U.S. Pat. No. 3,555,155) and Stanley O. et al. (Canadian Patent No.717,979).

The U.S. Pat. and Brit. Pat. of J. Krapcho relate to2-phenyl-3-oxo-1,4-benzothiazine in which phenyl nucleus isunsubstituted or substituted by halogen, and the pharmacological effectis for the treatment of Parkinsonism.

The U.S. Pat. of Stearns et al. relates to 2-(alkoxyphenyl)benzothiazinederivatives and the pharmacological effect is for the control ofinsects.

The Can. Pat. of Stanley et al. relates to2-(unsubstitutedphenyl)benzothiazine derivatives and the pharmacologicaleffects are for anticholinergic and antihistaminic.

The compounds of this invention are not only new in chemical structurebut also found useful for treatment of cardiovascular diseases and sucheffect on cardiovascular diseases has not been found in the known2-phenyl-3-oxo-1,4-benzothiazine derivatives.

Cardiovascular diseases are angina cordis, arrhythmia, thrombosis, etc.,and β-blocker, inhibitor of platelet aggregation, calcium antagonist,etc., are used as therapeutic agent.

From the pharmacological tests, it is proved that the compounds of thisinvention possess superior platelet antiaggregation effect and calciumantagonistic effect, so they are useful for cardiovascular diseases.

Processes for preparing the compounds of this invention are summarizedas follows and explained in detail by working examples.

First step is shown by the following schema. ##STR7## wherein X ishalogen or methanesulfonyloxy.

This reaction is Friedel-Crafts like reaction, which is performedwithout specific catalyst, but if necessary, using Lewis acid such asAlCl₃ as catalyst.

According to the varieties of the substituents, the following reactions[(1)-(3)] may be followed. (1) First case: R¹ in the formula [I] ishydroxy (represented by the formula [IV]).

The compound [IV] is reacted with halide of the formula [V] to producethe compound of the formula [VI], ##STR8## wherein --OH group and R⁴ maybe joined to form epoxy ring.

This reaction is performed in the presence of base such as sodiumhydride, sodium ethoxide, sodium hydroxide, etc.

(1)-(a) When R⁴ in the formula [VI] represents halogen (formula [VII]),if necessary, the compound is reacted with amine derivative of theformula [VIII] to produce the compound of the formula [IX], ##STR9##wherein R⁹ is ##STR10##

This reaction is performed with or without base (sodium carbonate,potassium hydroxide, triethylamine, etc.) in organic solvent (benzene,ethanol, dimethylformamide, etc.) or without solvent, and, if necessary,in the presence of catalyst such as sodium iodide.

(2) Second case: R³ in the formula [I] is hydrogen (represented by theformula [X]).

The compound of the formula [X] is reacted with halide of the formula[XI] to produce the compound of the formula [XII]. ##STR11##

This reaction is performed in the presence of base such as sodiumhydride, sodium ethoxide, sodium hydroxide, etc.

(2)-(a) When R⁵ in the formula [XII] is hydroxy, if necessary, thecompound [XII] is esterified by diazoalkane (diazomethane, etc.), alkylhalide and base, or alcohol and acid. If R¹ and/or R² in the formula[XII] are/is hydroxy, the hydroxy group(s) may be converted to alkoxygroup(s) in the esterification step. Said ester in which R¹ and/or R²are/is converted to alkoxy, if necessary, is hydrolized with base.

(2)-(b) When R⁵ in the formula [XII] is hydroxy (represented by theformula [XIII]), if necessary, the compound [XIII] is reacted with aminederivative of the formula [XIII] to produce the compound of the formula[XIV]. ##STR12##

This reaction is performed by Schotten-Baumann method, mixed anhydridemethod or DCC method which is widely used in peptide synthesis.

When R¹ and/or R² are/is hydroxy, the hydroxy group(s) may be previouslyprotected by (C₁ -C₆) alkanoyl or tetrahydropyranyl and the protectivegroup(s) can be removed by hydrolysis.

(2)-(c) When R¹ in the formula [XIV] is hydroxy (represented by theformula [XV]), if necessary, followed by the reaction with halide of theformula [V] which produces the compound of the formula [XVI]. ##STR13##

This reaction is performed in the presence of base such as sodiumhydride, sodium ethoxide, sodium hydroxide, etc.

(2)-(d) When R⁴ in the formula [XVI] is halogen (represented by theformula [XVII]), if necessary, further followed by the reaction withamine derivative of the formula [XVIII] which produce the compound ofthe formula [XIX]. ##STR14## wherein R¹⁰ is ##STR15## This reaction isperformed in the presence of base such as sodium hydride, sodiumethoxide, sodium hydroxide, etc.

(3) Third case: In the formula [I], R¹ is hydroxy, R³ is hydrogen, and##STR16## represent the same structure.

The compound of the formula [XX] is reacted with halide of the formula[XXI] to produce the compound of the formula [XXII]. ##STR17## wherein##STR18## are represented by R¹¹.

This reaction is performed, using excess amount of halide of the formula[XXI], in the presence of base such as sodium hydride, sodium ethoxide,sodium hydroxide, etc.

(3)-(a) When R¹¹ in the formula [XXII] is (C₁ -C₆)alkyl containinghalogen (represented by the formula [XXIII]), if necessary, followed bythe reaction with amine derivative of the formula [VIII] which producesthe compound of the formula [XXIV]. ##STR19## wherein Alk is (C₁-C₆)alkylene.

This reaction is performed using excess amount of amine derivative ofthe formula [VIII] which plays a role of base.

The compounds of this invention can be converted to acid salts. Saidsalts are obtained by usual methods using inorganic or organic acids.Examples of pharmaceutically acceptable salts of the compounds arehydrochloric acid salt, sulfuric acid salt, phosphoric acid salt, lacticacid salt, maleic acid salt, fumaric acid salt, oxalic acid salt, citricacid salt, methanesulfonic acid salt, benzoic acid salt,p-toluenesulfonic acid salt, etc. The compounds of this invention can bealso converted to metal salt or amine salt such as sodium salt,potassium salt, calcium salt, ammonium salt, diethylamine salt,triethanolamine salt, etc.

The compounds of this invention have stereoisomers because of theexistence of one or more asymmetric carbon atoms, and these isomers areincluded in this invention.

Examples are shown below, and the compounds are listed in Table 1-13.

EXAMPLE 1

3,4-Dihydro-2-(4-hydroxyphenyl)-3-oxo-2H-1,4-benzothiazine (compound No.2)

To a stirred solution of 2-chloro-3,4-dihydro-3-oxo-2H-1,4-benzothiazine(30 g) and phenol (17 g) in anhydrous CH₂ Cl₂ (400 ml), AlCl₃ (24 g) isadded by portions under ice-cooling.

The mixture is stirred for 3 hours under ice-cooling and for 2 hours atroom temperature, and then poured into ice-water (500 ml). Crystals arecollected by filtration to give 30.6 g (79%) of the titled compound.

Physical data are shown in Table 1.

The compounds shown in Table 1 and 2 are prepared by the similar method.

EXAMPLE 2

3,4-Dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine(compound No. 3)

To a stirred solution of p-methoxyphenol (37.4 g) in anhydrous CH₂ Cl₂(290 ml), 2-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine (53.6g) is added. The mixture is stirred for 3.5 hours at room temperature.Crystals are collected by filtration to give 56.7 g (75%) of the titledcompound.

Physical data are shown in Table 1.

The compounds shown in Table 1 and 2 are prepared by the similar method.

EXAMPLE 3

3,4-Dihydro-4-(3-dimethylaminopropyl)-2-(2-hydroxyphenyl)-3-oxo-2H-1,4-benzothiazine(compound No. 6) and

3,4-dihydro-4-(3-dimethylaminopropyl)-2-(4-hydroxyphenyl)-3-oxo-2H-1,4-benzothiazine(compound No. 71)

To a stirred solution of2-chloro-3,4-dihydro-4-(3-dimethylaminopropyl)-3-oxo-2H-1,4-benzothiazine(20 g) and phenol (7 g) in anhydrous CH₂ Cl₂ (200 ml), AlCl₃ (10 g) isadded under ice-cooling. The mixture is stirred for 3 hours at roomtemperature and poured into ice-water. The aqueous layer is washed withether and alkalifized with 6N NaOH. The separated oil is extracted withethyl acetate and the organic layer is washed with water and saturatedsodium chloride solution. The ethyl acetate solution is dried overanhydrous magnesium sulfate and concentrated in vacuo. The residue ischromatographed on silica gel to give 1.7 g (8%) of compound No. 6 and8.5 g (40%) of compound No. 7.

Physical data are shown in Table 1.

The compound shown in Table 1 is prepared by the similar method.

EXAMPLE 4

[3,4-Dihydro-2-(2-hydroxy-5-nitrophenyl)-3-oxo-2H-1,4-benzothiazin-4-yl]aceticacid (compound No. 16)

To a stirred solution of(2-chloro-3,4-dihydro-3-oxo-1,4-yl-4-benzothiazine)acetic acid (7 g) andp-nitrophenol (4.6 g) in anhydrous CH₂ Cl₂ (70 ml), AlCl₃ (4.4 g) isadded. The mixture is stirred under reflux for 8.5 hours, and pouredinto ice-water and then decantated to give gummy substance. The gummysubstance is dissolved in potassium carbonate solution and filtered. Thefiltrate is washed with CHCl₃ and acidified with conc. HCl. Theseparated oil is extracted with ethyl acetate and the organic layer iswashed with saturated sodium chloride solution. The solution is driedover anhydrous sodium sulfate and concentrated in vacuo. Ethanol andbenzene are added to the residue to give crystals. The crystals arecollected by filtration to give 4 g (41%) of the titled compound.

Physical data are shown in Table 2.

EXAMPLE 5

3,4-Dihydro-3-oxo-2-[4-[(tetrahydropyran-2-yl)oxy]phenyl]-2H-1,4-benzothiazine(compound No. 5)

To a stirred solution of3,4-dihydro-2-(4-hydroxyphenyl)-3-oxo-2H-1,4-benzothiazine (compound No.2, 14 g) and 2,3-dihydropyrane (37.2 ml) in ethyl acetate (120 ml),ethyl acetate (13.6 ml) saturated with HCl gas is added and standedovernight. Saturated sodium hydrogen carbonate solution is added to themixture and separated crystals are collected by filtration. Ethylacetate layer of the filtrate is concentrated in vacuo after drying oversodium sulfate. The residue and the crystals are mixed and purified bysilica gel column chromatography to give 13.6 g (73%) of the titledcompound.

Physical data are shown in Table 1.

EXAMPLE 6

3,4-Dihydro-4-(3-dimethylaminopropyl)-2-(4-hydroxyphenyl)-3-oxo-2H-1,4-benzothiazine(compound No. 7)

To a stirred solution of 50% sodium hydride (0.37 g) in anhydrousdimethylformamide (20 ml),3,4-dihydro-3-oxo-2-[4-[(tetrahydropyran-2-yl)oxy]phenyl]-2H-1,4-benzothiazine(compound No. 5, 3 g) dissolved in anhydrous dimethylformamide (20 ml)is added under nitrogen atmosphere and ice-cooling, and stirred for 25minutes. To the mixture, anhydrous dimethylformamide solution ofγ-dimethylaminopropyl chloride (prepared from 1.53 g ofγ-dimethylaminopropyl chloride hydrochloride and 1.35 ml oftriethylamine) is added. The reaction mixture is stirred for 2.5 hoursat room temperature and 2 hours at 75° C., poured into a mixture of NHCl and ice-water, and washed with ethyl acetate. The aqueous layer isalkalifized with 30% NaOH and extracted with ethyl acetate. The organiclayer is washed with water, dried over anhydrous sodium sulfate andconcentrated in vacuo. Ethyl acetate is added to the residue. Separatedcrystals are collected by filtration to give 2.05 g (68%) of the titledcompound.

Physical data are shown in Table 1.

The compounds shown in Table 2 and 3 are prepared by the similar method.

EXAMPLE 7

[3,4-Dihydro-2-(4-methoxyphenyl)-3-oxo-2H-1,4-benzothiazin-4-yl]aceticacid methyl ester (compound No. 32)

To a solution of[3,4-dihydro-2-(4-hydroxyphenyl)-3-oxo-2H-1,4-benzothiazin-4-yl]aceticacid (compound No. 17, 2.5 g) in ethyl acetate (10 ml), diazomethanedissolved in ether is added and standed overnight. The mixture isconcentrated in vacuo and the residue is purified by silica gel columnchromatography to give 2.5 g (92%) of the titled compound.

Physical data are shown in Table 2.

The compounds shown in Table 2 are prepared by the similar method.

EXAMPLE 8

[3,4-Dihydro-2-(2,5-dimethoxyphenyl)-3-oxo-2H-1,4-benzothiazin-4-yl]aceticacid methyl ester (compound No. 29)

To a solution of[3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-3-oxo-2H-1,4-benzothiazin-4-yl]aceticacid (compound No. 14, 2.5 g) in ethyl acetate (20 ml) containing onedrop of fluoboric acid, diazomethane dissolved in ether is added andstanded overnight. The mixture is concentrated in vacuo to give 1.9 g(70%) of the titled compound.

Physical data are shown in Table 2.

The compounds shown in Table 2 are prepared by the similar method.

EXAMPLE 9

[3,4-Dihydro-2-(2,5-dimethoxyphenyl)-3-oxo-2H-1,4-benzothiazin-4-yl]aceticacid (compound No. 20)

To the solution of[3,4-dihydro-2-(2,5-dimethoxyphenyl)-3-oxo-2H-1,4-benzothiazin-4-yl]aceticacid methyl ester (compound No. 29, 1.4 g) in methanol (20 ml), 2N NaOH(4 ml) is added and stirred for 1 hour. To the mixture, water (50 ml) isadded and acidified with N HCl. The reaction product is extracted withethyl acetate. The orgenic layer is washed with saturated sodiumchloride solution, dried over anhydrous sodium sulfate and concentratedin vacuo. Benzene is added to the residue and separated crystals arecollected by filtration to give 0.85 g (63%) of the titled compound.

Physical data are shown in Table 2.

The compounds shown in Table 2 are prepared by the similar method.

EXAMPLE 10

[2-(4-Acetoxyphenyl)-3,4-dihydro-3-oxo-2H-1,4-benzothiazin-4-yl]aceticacid (compound No. 26)

To a solution of[3,4-dihydro-2-(4-hydroxyphenyl)-3-oxo-2H-1,4-benzothiazin-4-yl]aceticacid (compound No. 17, 49.2 g) in pyridine (150 ml), acetic anhydride(22 ml) is added and the mixture is standed overnight. The reactionmixture is poured into a mixture of 6N HCl and ice, and the separatedoil is extracted with ethyl acetate. The organic layer is washed with NHCl, dried over anhydrous sodium sulfate and concentrated in vacuo.Benzene and ether are added to the residue and separated crystals arecollected by filtration to give 34.9 g (63%) of the titled compound.

Physical data are shown in Table 2.

The compound shown in Table 2 is prepared by the similar method.

EXAMPLE 11

[2-(4-Acetoxyphenyl)-3,4-dihydro-3-oxo-2H-1,4-benzothiazin-4-yl]acetamide(compound No. 37)

To a stirred solution of[2-(4-acetoxyphenyl)-3,4-dihydro-3-oxo-2H-1,4-benzothiazin-4-yl]aceticacid (compound No. 26, 4.6 g) and triethylamine (1.8 ml) in CH₂ Cl₂ (45ml), isobutylchloroformate (1.7 ml) is added dropwise at -12° C. Afterthe addition, the reaction mixture is stirred for 10 minutes at the sametemperature. Conc. ammonia water (7.2 ml) is added to the mixture. Themixture is stirred for 30 minutes at room temperature, and washed withsaturated sodium hydrogen carbonate solution and N HCl. The organiclayer is dried over anhydrous sodium sulfate and concentrated in vacuoto give 3.5 g (76%) of the titled compound.

Physical data are shown in Table 3.

The compounds shown in Table 3 are prepared by the similar method.

EXAMPLE 12[3,4-Dihydro-2-(4-hydroxyphenyl)-3-oxo-2H-1,4-benzothiazin-4-yl]acetamide(compound No. 35)

To a stirred solution of[2-(4-acetoxyphenyl)-3,4-dihydro-3-oxo-2H-1,4-benzothiazin-4-yl]acetamide(compound No. 37, 3.5 g) in dioxane (20 ml) and ethanol (30 ml), 2N NaOH(25 ml) is added under ice-water cooling. The mixture is stirred for 5minutes and acidified with 6N HCl. The separated oil is extracted withethyl acetate and the organic layer is washed with saturated sodiumhydrogen carbonate. The organic layer is dried over anhydrous sodiumsulfate and concentrated in vacuo.

Benzene is added to the residue and separated crystals are collected byfiltration to give 2.4 g (78%) of the titled compound.

Physical data are shown in Table 3.

The compound shown in Table 3 are prepared by the similar method.

EXAMPLE 13

3,4-Dihydro-2-(4-hydroxyphenyl)-4-morpholinocarbonylmethyl-3-oxo-2H-1,4-benzothiazine(compound No. 45)

To a stirred solution of[2-(4-acetoxyphenyl)-3,4-dihydro-3-oxo-2H-1,4-benzothiazin-4-yl]aceticacid (compound No. 26, 4 g) and triethylamine (1.6 ml) in anhydrous CH₂Cl₂ (40 ml), isobutylchloroformate (1.5 ml) is added dropwise at -12° C.After the addition, the reaction mixture is stirred for 15 minutes atthe same temperature. Morpholine (4.9 ml) is added to the mixture andthe mixture is stirred for 1.5 hours at room temperature and poured into2N NaOH. The aqueous layer is acidified with N HCl and separatedcrystals are collected by filtration. The crystals are washed withsodium hydrogen carbonate solution, water and ethanol to give 2.08 g(48%) of the titled compound.

Physical data are shown in Table 3.

The compounds shown in Table 3 are prepared by the similar method.

EXAMPLE 14

3,4-Dihydro-4-[4-(2-hydroxyethyl)piperazinocarbonylmethyl]-2-(4-hydroxyphenyl)-3-oxo-2H-1,4-benzothiazine(compound No. 44)

To a stirred solution of[2-(4-acetoxyphenyl)-3,4-dihydro-3-oxo-2H-1,4-benzothiazin-4-yl]aceticacid (compound No. 26, 2.9 g) and triethylamine (1.2 ml) in anhydrousCH₂ Cl₂ (30 ml), isobutylchloroformate (1.1 ml) is added dropwise at-18° C. After the addition, the reaction mixture is stirred for 20minutes at the same temperature.1-[2-[(Tetrahydropyran-2-yl)oxy]ethyl]piperazine (2.6 g) is added to themixture, and the mixture is stirred for 2.5 hours at room temperature,poured into N HCl and washed with ethyl acetate. The aqueous layer isalkalifized with 2N NaOH and stirred for 1 hour. The separated oil isextracted with ethyl acetate, and the organic layer is washed withwater, dried over anhydrous sodium sulfate and concentrated in vacuo.CHCl₃ is added to the residue and separated crystals are collected byfiltration to give 2.4 g (69%) of the titled compound.

Physical data are shown in Table 3.

EXAMPLE 15

3,4-Dihydro-2-[2-(2,3-epoxypropoxy)-5-methoxyphenyl]-3-oxo-2H-1,4-benzothiazine(compound No. 10)

To a stirred solution of3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-3-oxo-2H-1,4-benzothiazine(compound No. 1, 5.2 g) in methanol (30 ml), N NaOH (26 ml) andepichlorohydrine (7 ml) are added. The reaction mixture is stirred for30 minutes at 50° C. and overnight at room temperature.

Ethyl acetate is added to the mixture, and the organic layer is washedwith saturated sodium chloride solution, dried over anhydrous sodiumsulfate and concentrated in vacuo. The residual oil is purified bysilica gel column chromatography to give 2.9 g (47%) of the titledcompound.

Physical data are shown in Table 1.

The compounds shown in Table 1 and 3 are prepared by the similar method.

EXAMPLE 16

[3,4-Dihydro-2-[2-(2,3-epoxypropoxy)-5-methoxyphenyl]-3-oxo-2H-1,4-benzothiazin-4-yl]acetamide(compound No. 39)

To a solution of 50% sodium hydride (0.19 g) in anhydrousdimethylformamide (5 ml),[3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-3-oxo-2H-1,4-benzothiazin-4-yl]acetamide(compound No. 34, 1.5 g) in anhydrous dimethylformamide (15 ml) is addedunder nitrogen atmosphere. After the addition, epichlorohydrine (1.4 ml)is added to the reaction mixture, and the mixture is stirred for 1 hourat room temperature and for 30 minutes at 50° C. The mixture is pouredinto ice-water and the separated oil is extracted with ethyl acetate.The organic layer is washed with water, N NaOH and water, dried overanhydrous sodium sulfate and concentrated in vacuo. Methanol andisopropylether are added to the residue and separated crystals arecollected by filtration to give 1.39 g (80%) of the titled compound.

Physical data are shown in Table 3.

The compounds shown in Table 1 and 3 are prepared by the similar method.

EXAMPLE 17

2-[2-(3-Chloropropoxy)-5-methoxyphenyl]-3,4-dihydro-2H-1,4-benzothiazine(compound No. 46)

To a stirred solution of 50% sodium hydride (6.2 g) in anhydrousdimethylformamide (20 ml),3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-3-oxo-2H-1,4-benzothiazine(compound No. 1, 28.7 g) dissolved in anhydrous dimethylformamide (100ml) is added dropwise. After the addition, 3-chloropropylbromide (31.5g) dissolved in anhydrous ethanol (50 ml) is added and the reactionmixture is stirred continuously for 6 hours. The mixture is poured intowater (800 ml) and separated oil is extracted with ethyl acetate (300ml). The organic layer is washed with water and saturated sodiumchloride solution, dried over anhydrous sodium sulfate and concentratedin vacuo. The residual oil is purified by silica gel columnchromatography to give 15.6 g (43%) of the titled compound.

Physical data are shown in Table 4.

The compounds shown in Table 4,5 and 9 are prepared by the similarmethod.

EXAMPLE 18

3,4-Dihydro-2-[4-(3-dimethylaminopropoxy)phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine(compound No. 72)

To a stirred solution of 50% sodium hydride (1.2 g) in anhydrousdimethylformamide (5 ml),3,4-dihydro-2-(4-hydroxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine(compound No. 4, 3.0 g) and 3-dimethylaminopropyl chloride (2.1 g)dissolved in anhydrous dimethylformamide (12 ml) are added dropwiseunder nitrogen atmosphere.

After the addition, the reaction mixture is stirred for 1 hour at roomtemperature and for 3.5 hours at 85°-90° C., and poured into water (100ml). Reaction product is extracted with benzene, and the organic layeris washed with N KOH and saturated sodium chloride solution, dried overanhydrous sodium sulfate and concentrated in vacuo. The residual oil ispurified by silica gel column chromatographyl to give 1.5 g (38%) of thetitled compound.

Physical data are shown in Table 7.

The compounds shown in Table 6, 7, and 9-12 are prepared by the similarmethod.

EXAMPLE 19

3,4-Dihydro-2-[5-methoxy-2-[4-(N-methylcyclohexylamino)butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazineoxalate (compound No. 63)

3,4-Dihydro-2-[2-(4-bromobutoxy)-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine(compound No. 50, 1.1 g) and N-methylcyclohexylamine (3.4 g) aredissolved in benzene (1 ml), and the mixture is stirred for 2 hours at105°-110° C. After cooling, N HCl (30 ml) is added to the mixture andthe reaction product is extracted with chloroform. The organic layer iswashed with N HCl, water and N NaOH, dried over anhydrous sodium sulfateand concentrated in vacuo. The residual oil is dissolved in ethylacetate (30 ml). Oxalic acid (0.3 g) dissolved in ethyl acetate (10 ml)is added to the solution with stirring. Separated crystals are collectedby filtration to give 1.1 g (78%) of the titled compound.

Physical data are shown in Table 6.

The compounds shown in Table 6-11 are prepared by the similar method.

EXAMPLE 20

3,4-Dihydro-2-[5-methoxy-2-[3-[4-(3,4,5-trimethoxyphenethyl)piperazino]propoxy]phenyl]-3-oxo-2H-1,4-benzothiazinehydrochloride (compound No. 74)

Acetone (10 ml) solution of2-[2-(3-chloropropoxy)-5-methoxyphenyl]-3,4-dihydro-3-oxo-2H-1,4-benzothiazine(1.0 g) and sodium iodide (0.4 g) is refluxed for 30 minutes.Precipitate is filtered off and the filtrate is concentrated in vacuo.To the residue, 1-(3,4,5-trimethoxyphenetyl)piperazine (1.0 g), sodiumcarbonate (0.5 g) and toluene (5 ml) are added and the mixture isrefluxed for 4 hours. After cooling, chloroform (30 ml) is added to thereaction mixture. The organic layer is washed with N HCl, N NaOH andsaturated sodium chloride solution, dried over sodium sulfate andconcentrated in vacuo. The residual oil is dissolved in ethyl acetate,and to the solution HCl/ethyl acetate is added. Separated crystals arecollected by filtration to give 1.2 g (64%) of the titled compound.

Physical data are shown in Table 8.

The compounds shown in Table 6-12 are prepared by the similar method.

EXAMPLE 21

2-[4-(3-Chloropropoxy)phenyl]-3,4-dihydro-4-(3-dimethylaminopropyl)-3-oxo-2H-1,4-benzothiazine(compound No. 88)

To a stirred solution of 50% sodium hydride (0.33 g) in anhydrousdimethylformamide (10 ml),3,4-dihydro-4-(3-dimethylaminopropyl)-2-(4-hydroxyphenyl)-3-oxo-2H-1,4-benzothiazine(comopund No. 7, 2.15 g) dissolved in anhydrous dimethylformamide (10ml) is added dropwise and the reaction mixture is stirred for 15minutes. To the mixture, 1-bromo-3-chloropropane (2.27 g) dissolved inanhydrous ethanol (7 ml) is added and the mixture is stirred for 2 hoursat room temperature and for 3 hours at 40° C. The mixture is poured intoice-water and the reaction product is extracted with ethyl acetate. Theorganic layer is washed with N NaOH, water and saturated sodium chloridesolution, dried over anhydrous magnesium sulfate and concentrated invacuo. The residue is purified by silica gel column chromatography togive 1.31 g (50%) of the titled compound.

The physical data are shown in Table 10.

The compounds shown in Table 4, 5 and 10-11 are prepared by the similarmethod.

EXAMPLE 22

4-(6-Chlorohexyl)-2-[4-(6-chlorohexyloxy)phenyl]-3,4-dihydro-3-oxo-2H-1,4-benzothiazine(compound No. 87)

To a stirred solution of 50% sodium hydride (1.0 g) in anhydrousdimethylformamide (5 ml),3,4-dihydro-2-(4-hydroxyphenyl)-3-oxo-2H-1,4-benzothiazine (compound No.2, 2.6 g) dissolved in anhydrous dimethylformamide (12 ml) is addeddropwise under nitrogen atmosphere and the reaction mixture is stirredfor 5 minutes. To the mixture, 6-chlorohexyl methanesulfonate (5.1 g) isadded, and the mixture is stirred for 3 hours at room temperature andpoured into ice-water. The reaction product is extracted with ethylacetate.

The organic layer is washed with N KOH, water and saturated sodiumchloride solution, dried over magnesium sulfate and concentrated invacuo. The residue is purified by silica gel column chromatography togive 3.5 g (70%) of the titled compound.

Physical data are shown in Table 10.

The compounds shown in Table 9 and 10 are prepared by the similarmethod.

EXAMPLE 23

3,4-Dihydro-2-[2-(3-dimethylaminopropoxy)-5-methoxyphenyl]-4-(3-dimethylaminopropyl)-3-oxo-2H-1,4-benzothiazinedioxalate (compound No. 82)

To a stirred solution of 50% sodium hydride (3 g) in anhydrousdimethylformamide, anhydrous ethanol (10 ml) is added dropwise. To themixture,3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-3-oxo-2H-1,4-benzothiazine(compound No. 1, 4 g) dissolved in anhydrous dimethylformamide (15 ml)and then γ-dimethylaminopropyl chloride hydrochloride (5 g) dissolved inanhydrous dimethylformamide (12 ml) is added, and the reaction mixtureis stirred for 5.5 hours at 60° C. The mixture is poured into water andthe reaction product is extracted with ethyl acetate. The organic layeris washed with N KOH, water and saturated sodium chloride solution,dried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue is purified by silica gel column chromatography to give 4.2 g(66%) of the titled compound as free form.

The product is dissolved in ethyl acetate, and to the solution oxalicacid is added to give 5.1 g (57%) of the titled compound.

Physical data are shown in Table 9.

The compounds shown in Table 9 and 10 are prepared by the similarmethod.

EXAMPLE 24

3,4-Dihydro-4-(5-dimethylaminopentyl)-2-[2-(5-dimethylaminopentyloxy)-5-methoxyphenyl]-3-oxo-2H-1,4-benzothiazinedicitrate (compound No. 84)

A mixture of4-(5-bromopentyl)-2-[2-(5-bromopentyloxy)-5-methoxyphenyl]-3,4-dihydro-3-oxo-2H-1,4-benzothiazine(compound No. 80, 0.55 g), 40% dimethylamine aqueous solution (1.3 ml)and benzene (1 ml) is refluxed for 4.5 hours with stirring. Chloroformis added to the reaction mixture, and the organic layer is washed withwater, N NaOH and saturated sodium chloride solution, dried overanhydrous magnesium sulfate and concentrated in vacuo. The residue ispurified by silica gel column chromatography to give 0.3 g (62%) of thetitled compound as free form. The product is dissolved in ethyl acetate,and to the solution citric acid is added to give 0.35 g (41%) of thetitled compound.

Physical data are shown in Table 9.

The compounds shown in Table 9 and 10 are prepared by the similarmethod.

EXAMPLE 25

[3,4-Dihydro-2-[2-(3-dimethylaminopropoxy)-5-methoxyphenyl]-3-oxo-2H-1,4-benzothiazin-4-yl]acetamide(compound No. 93)

To a stirred solution of[2-[2-(3-chloropropoxy)-5-methoxyphenyl]-3-oxo-2H-1,4-benzothiazin-4-yl]acetamide(compound No. 92, 1.5 g) and potassium iodide (0.3 g) indimethylformamide (5 ml), 40% aqueous dimethylamine (2.4 ml) is added.The reaction mixture is stirred for 2.5 hours at 60° C. and poured intowater. The reaction product is extracted with ethyl acetate. The organiclayer is washed with water, dried over anhydrous sodium sulfate andconcentrated in vacuo. Benzene is added to the residue and separatedcrystals are collected by filtration to give 1.22 g (80%) of the titledcompound.

Physical data are shown in Table 11.

The compounds shown in Table 11 and 12 are prepared by the similarmethod.

EXAMPLE 26

3,4-Dihydro-4-[[4-(ethoxycarbonyl)piperazino]carbonylmethyl]-2-[4-[3-[4-(4-fluorobenzoyl)piperizino]propoxy]phenyl]-3-oxo-2H-1,4-benzothiazine(compound No. 104)

A solution of2-[4-(3-chloropropoxy)phenyl]-3,4-dihydro-4-[[4-(ethoxycarbonyl)piperazino]carbonylmethyl]-3-oxo-2H-1,4-benzothiazine(compound No. 103, 0.9 g) and sodium iodide (0.25 g) in acetone (5 ml)is refluxed for 1 hour. Precipitate is filtered off and the filtrate isconcentrated in vacuo.

To the residue, 4-(4-fluorobenzoyl)piperidine (0.7 g), potassiumcarbonate (0.51 g) and dimethylformamide (5 ml) are added and themixture is stirred for 1 hour at 50° C. The mixture is poured into waterand the reaction product is extracted with chloroform. The organic layeris washed with water, dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue is purified by silica gel columnchromatography to give 0.79 g (66%) of the titled compound.

Physical data are shown in Table 12.

EXAMPLE 27

2-[2-(3-tert-Butylamino-2-hydroxypropoxy)-5-methoxyphenyl]-3,4-dihydro-3-oxo-2H-1,4-benzothiazine(compound No. 105)

3,4-Dihydro-2-[2-(2,3-epoxypropoxy)-5-methoxyphenyl]-3-oxo-2H-1,4-benzothiazine(compound No. 10, 0.8 g) and tert-butylamine (2.5 ml) are dissolved inethanol (15 ml). The solution is refluxed for 1.5 hours, and aftercooling, concentrated in vacuo. The residue is dissolved in chloroform,and the solution is washed with 2N HCl, water and N NaOH. The organiclayer is dried over anhydrous sodium sulfate and concentrated in vacuoto give 0.9 g (93%) of the titled compound.

Physical data are shown in Table 13.

The compounds shown in Table 13 are prepared by the similar method.

EXAMPLE 28

3,4-Dihydro-2-[5-methoxy-2-[2-hydroxy-3-(4-phenacylpiperazino)propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazinedimaleate (compound No. 107)

3,4-Dihydro-2-[2-(2,3-epoxypropoxy)-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine(compound No. 11, 1.6 g) and phenacylpiperazine (1.0 g) are dissolved intoluene (1 ml). The solution is stirred for 1.5 hours at 110°-120° C.After cooling, 2N HCl (10 ml) is added to the reaction mixture andstirred. Supernatant liquid is removed off by decantation. To theresidual gummy product, chloroform (30 ml) and N NaOH (15 ml) are added.The organic layer is dried over anhydrous sodium sulfate andconcentrated in vacuo. To the residual oil dissolved in ethyl acetate,maleic acid (1.1 g) is added. Separated crystals are collected byfiltration to give 3.0 g (84%) of the titled compound.

Physical data are shown in Table 13.

EXAMPLE 29

3,4-Dihydro-2-[2-(3-dimethylaminopropoxy)-5-methoxyphenyl]-4-(3-dimethylaminopropyl)-3-oxo-2H-1,4-benzothiazinedioxalate (compound No. 82)

To a stirred solution of 50% sodium hydride (0.24 g) in anhydrousdimethylformamide (5 ml),3,4-dihydro-2-[2-(3-dimethylaminopropoxy)-5-methoxyphenyl]-3-oxo-2H-1,4-benzothiazine(compound No. 55, 0.74 g) dissolved in anhydrous dimethylformamide (5ml) is added dropwise under nitrogen atmosphere, and the mixture isstirred continuously for 10 minutes.

To the reaction mixture, γ-dimethylaminopropyl chloride hydrochloride(0.47 g) dissolved in anhydrous dimethylformamide (3 ml) is added andthe mixture is stirred overnight at room temperature. The mixture ispoured into water and the reaction product is extracted with ethylacetate. The organic layer is washed with N KOH, water and saturatedsodium chloride solution, dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue is purified by silica gel columnchromatography. The product is dissolved in ethyl acetate, and to thesolution oxalic acid is added to give 1.1 g (87%) of the titledcompound.

Physical data are shown in Table 9.

Following compounds can be prepared by similar methods described inExample 1-29.

3,4-Dihydro-4-(3-dimethylaminopropyl)-2-[2-[3-(N-methylcyclohexylamino)propoxy]-5-methoxyphenyl]-3-oxo-2H-1,4-benzothiazine

3,4-Dihydro-4-(3-dimethylaminopropyl)-2-[2-[4-(N-methylcyclohexylamino)butoxy]-5-methoxyphenyl]-3-oxo-2H-1,4-benzothiazine

3,4-Dihydro-2-[2-(4-dimethylaminobutoxy)-5-methoxyphenyl]-4-(3-dimethylaminopropyl)-3-oxo-2H-1,4-benzothiazine

3,4-Dihydro-4-(3-dimethylaminopropyl)-2-[4-[3-(N-methylcyclohexylamino)propoxy]phenyl]-3-oxo-2H-1,4-benzothiazine

3,4-Dihydro-4-(3-dimethylaminopropyl)-2-[4-[4-(N-methylcyclohexylamino)butoxy]phenyl]-3-oxo-2H-1,4-benzothiazine

3,4-Dihydro-2-[4-(4-dimethylaminobutoxy)phenyl]-4-(3-dimethylaminopropyl)-3-oxo-2H-1,4-benzothaizine

2-[2-[4-(4-Benzoylpiperidino)butoxy]-5-methoxyphenyl]-3,4-dihydro-4-(3-dimethylaminopropyl)-3-oxo-2H-1,4-benzothiazine

3,4-Dihydro-4-(3-dimethylaminopropyl)-2-[5-methoxy-2-[4-[4-(3,4,5-trimethoxyphenethyl)piperazino]butoxy]phenyl]-3-oxo-2H-1,4-benzothiazine

3,4-Dihydro-4-(3-dimethylaminopropyl)-2-[2-[4-[4-(4-fluorobenzoyl)piperidino]butoxy]-5-methoxyphenyl]-3-oxo-2H-1,4-benzothiazine

2-[4-(3-tert-Butylamino-2-hydroxypropoxy)phenyl]-3,4-dihydro-3-oxo-2H-1,4-benzothiazine

3,4-Dihydro-2-[4-[3-(N-methylcyclohexylamino)propoxy]phenyl]-4-[3-(N-methylcyclohexylamino)propyl]-3-oxo-2H-1,4-benzothiazine

3,4-Dihydro-2-[4-[3-(N-methylcyclohexylamino)propoxy]phenyl]-3-oxo-2H-1,4-benzothiazine

3,4-Dihydro-2-[4-(3-dimethylaminopropoxy)phenyl]-4-[2-[4-(2-hydroxyethyl)piperazino]-2-oxoethyl]-3-oxo-2H-1,4-benzothiazine

[3,4-Dihydro-2-[2-[4-(N-methylcyclohexylamino)butoxy]-5-methoxyphenyl]-3-oxo-2H-1,4-benzothaizine-4-yl]-N,N-dimethylacetamide

3,4-Dihydro-2-[4-[3-[4-[2-hydroxy-2-(4-methoxyphenyl)ethyl]piperazino]propoxy]phenyl]-3-oxo-2H-1,4-benzothiazine

3,4-Dihydro-2-[4-[4-[4-(4-fluorobenzoyl)piperidino]butoxy]phenyl]-3-oxo-2H-1,4-benzothiazine

2-[4-[4-(4-Benzoylpiperidino)butoxy]phenyl]-3,4-dihydro-3-oxo-2H-1,4-benzothiazine

3,4-Dihydro-2-[2-[4-[4-(2-hydroxy-2-phenylethyl)piperazino]butoxy]-5-methoxyphenyl]-3-oxo-2H-1,4-benzothiazine

3,4-Dihydro-4-(3-dimethylaminopropyl)-2-[2-[4-[4-(2-hydroxy-2-phenylethyl)piperazino]butoxy]-5-methoxyphenyl]-3-oxo-2H-1,4-benzothiazine

                                      TABLE 1    __________________________________________________________________________     ##STR20##    Com-                          Method    pound                         (Example                                       Yield                                           mp    No. R.sup.3  R.sup.1     R.sup.2                                  No.) (%) (°C.)                                                   IR (KBr,    __________________________________________________________________________                                                   cm.sup.-1)    1   H        2-OH        5-OCH.sub.3                                  1    84  216-219 (dec.)                                                   3336, 1637, 1580, 1506,                                                   1473, 1427,                                  2    68  (DMFH.sub.2 O)                                                   1345, 1267, 1210, 1187,                                                   1047, 809,                                                   756, 645    2   H        4-OH        H    1    79  197-201 3280, 1636, 1608, 1579,                                                   1507, 1478,                                  2    57  (EtOH)  1390, 1265, 1244, 1219,                                                   831, 753    3   CH.sub.3 2-OH        5-OCH.sub.3                                  1    88  202-205 3280, 1629, 1582, 1508,                                                   1445, 1425,                                  2    75  (DMFH.sub.2 O)                                                   1374, 1302, 1266, 1202,                                                   1150, 1039,                                                   809, 749    4   CH.sub.3 4-OH        H    1    63  158-162 3272, 1637, 1610, 1583,                                                   1441, 1360,                                  2    51  (EtOH)  1217, 746, 690, 656                                  6    74    5   H                  ##STR21##  H    5    73  161-163 3200, 2928, 1665, 1581,                                                   1509, 1477, 1362, 1357,                                                   1234, 1174, 1032, 962m                                                   746    6   (CH.sub.2).sub.3 N(CH.sub.3).sub.2                 2-OH        H    2     3  161-165 (dec.)                                                   2940, 1654, 1581, 1445,                                                   1376, 1316,                                  3     8  (EtOH)  1271, 1250, 1223, 757    7   (CH.sub.2).sub.3 N(CH.sub.3).sub.2                 4-OH        H    2    25  158-160 2932, 1654, 1607, 1586,                                                   1473, 1466,                                  3    40          1443, 1368, 1257, 1240,                                                   1206, 1168,                                  6    68    8   (CH.sub.2).sub.3 N(CH.sub.3).sub.2                 2-OH        5-OCH.sub.3                                  2    83  oil     2944, 1735, 1656, 1509,                                                   1474,                                  3    91          1460, 1444, 1371, 1270,                                                   1225,                                                   1218, 1040, 750 (neat)    9   (CH.sub.2).sub.3 N(CH.sub.3).sub.2                  ##STR22##  H    15 16                                       36 56                                           amorph. 1661, 1608, 1584, 1509,                                                   750    10  H                  ##STR23##  5-OCH.sub.3                                  15 16                                       47 69                                           141-144 3184, 3044, 1663, 1237,                                                   1209, 798    11  CH.sub.3                  ##STR24##  5-OCH.sub.3                                  15 16                                       84 91                                           139-143 3050, 1643, 1242, 1217,    __________________________________________________________________________                                                   814

                                      TABLE 2    __________________________________________________________________________     ##STR25##    Compound             Method (Ex-                                Yield                                    mp    No.   R   R.sup.1                    R.sup.2                         ample No.)                                (%) (°C.)   IR (KBr,    __________________________________________________________________________                                                   cm.sup.-1)    12    H   2-OH  5-CH.sub.3                         1      80  182-183 (dec.) 3056, 1733, 1620, 1578,                                                   1509, 1479,                         2      75  (MeOHAcOEtC.sub.6 H.sub.6)                                                   1448, 1390, 1256, 1198,                                                   810, 750    13    H   2-OH  5-OH 1      57  211-211.5 (dec.)                                                   3276, 1725, 1653, 1364,                                                   1319, 1267,                         2      52  (MeOHH.sub.2 O)                                                   1207, 824, 750    14    H   2-OH  5-OCH.sub.3                         1      71  190-191 (dec.) 3084, 1751, 1734, 1625,                                                   1578, 1508,                         2      58  (EtOHC.sub.6 H.sub.6)                                                   1448, 1430, 1388, 1259,                                                   1193, 1042,                                                   751    15    H   2-OH  5-Cl 1      67  217 (dec.)     3400, 1708, 1642, 1583,                                                   1500, 1482,                         2      58  (MeOHAcOEtC.sub.6 H.sub.6)                                                   1445, 1408, 1368, 1282,                                                   1236, 1209,                                                   1107, 810, 749    16    H   2-OH  5-NO.sub.2                         1      18  253 (dec.)     3300, 1707, 1629, 1588,                                                   1524, 1500,                         2       3  (MeOHAcOEtC.sub.6 H.sub.6)                                                   1482, 1432, 1411, 1375,                                                   1335, 1285,                         4      41                 1248, 1213, 1080, 746,                                                   635    17    H   4-OH  H    1      83  188-191 (dec.) 3396, 3176, 3020, 1705,                                                   1654, 1608,                         2      75                 1369, 1265, 1240, 1206,                                                   749                         6      64     .sup. 18*.sup.1          H   4-OH  3-OH 1      60  136-138 (dec.) 3324, 1720, 1647, 1610,                                                   1527, 1479,                         2      53  (MeOHAcOEt)    1444, 1373, 1293, 1232,                                                   1197, 746     .sup. 19*.sup.2          H   2-OCH.sub.3                    5-CH.sub.3                         9      99  113-114 (dec.) 3048, 1722, 1661, 1501,                                                   1479, 1445,                                    (Et.sub.2 OC.sub.6 H.sub.6)                                                   1401, 1368, 1320, 1241,                                                   1214, 1202,                                                   1027, 806, 757, 691    20    H   2-OCH.sub.3                    5-OCH.sub.3                         9      63  144-146        3420, 1726, 1708, 1663,                                                   1500, 1482,                                    (CH.sub.2 Cl.sub.2Et.sub.2 OC.sub.6                                    H.sub.6)       1447, 1368, 1317, 1243,                                                   1222, 1042,                                                   753     .sup. 21*.sup.2          H   2-OCH.sub.3                    5-Cl 9      94  119-121 (dec.) 3056, 1720, 1661, 1479,                                                   1368, 1237,                                    (C.sub.6 H.sub.6)                                                   1217, 1193, 1023, 808,                                                   762, 693     .sup. 22*.sup.3          H   2-OCH.sub.3                    5-NO.sub.2                         9      99  186-188 (dec.) 3620, 3412, 1720, 1664,                                                   1587, 1505,                                    (CH.sub.3 COCH.sub.3CHCl.sub.3C.sub.6                                    H.sub.6)       1485, 1371, 1339, 1266,                                                   1237, 1190,                                                   1018, 757, 750     .sup. 23*.sup.4          H   4-OCH.sub.3                    H    9      67  58-61          3420, 1724, 1664, 1608,                                                   1581, 1510,                                    (Et.sub.2 OC.sub.6 H.sub.6)                                                   1478, 1447, 1367, 1314,                                                   1302, 1242,                                                   1207, 1175, 1024, 750,                                                   677     .sup. 24*.sup.5          H   4-OCH.sub.3                    3-OCH.sub.3                         9      80  208-210        3484, 1631, 1599, 1511,                                                   1478, 1439,                                                   1420, 1397, 1370, 1301,                                                   1281, 1260,                                                   1232, 1140, 1021, 749    25    H   2-OCOCH.sub.3                    5-OCH.sub.3                         10     86  amorph.        1750, 1741, 1735, 1663,                                                   1478, 1369,                                                   1189    26    H   4-OCOCH.sub.3                    H    10     63  170-172        3032, 3016, 2924, 1734,                                                   1718, 1658,                                                   1479, 1442, 1400, 1366,                                                   1196, 1167,                                                   749    27    H   4-N(CH.sub.3).sub.2                    H    1      34  amorph.        3408, 1719, 1660, 1609,                                                   1583, 1519,                         2      45                 1478, 1445, 1369, 1320,                                                   1201, 1161,                                                   748    28    CH.sub.3              2-OCH.sub.3                    5-CH.sub.3                         7      33  97-98          1744, 1663, 1502, 1365,                                                   1245, 1214,                         8      70  (MeOH)         1180, 1027, 803, 750    29    CH.sub.3              2-OCH.sub.3                    5-OCH.sub.3                         7      26  127.5-128.5    1744, 1738, 1655, 1498,                                                   1239, 1219,                         8      70  (CH.sub.2 Cl.sub.2MeOH)                                                   1180, 1035, 749    30    CH.sub.3              2-OCH.sub.3                    5-Cl 7      40  139-140        1744, 1664, 1366, 1241,                                                   1220, 1022,                         8      87  (AcOMeMeOH)    752    31    CH.sub.3              2-OCH.sub.3                    5-NO.sub.2                         7      52  187-188        1745, 1736, 1664, 1586,                                                   1510, 1369,                         8      99  (AcOMeMeOH)    1338, 1264, 1220, 1194,                                                   1089, 1017,                                                   825, 760, 750    32    CH.sub.3              4-OCH.sub.3                    H    7      92  oil            1747, 1668, 1609, 1584,                                                   1513, 1481,                         8      98                 1448, 1368, 1249, 1210,                                                   1178, 1028,                                                   750 (neat)    33    CH.sub.3              4-OCH.sub.3                    3-OCH.sub.3                         7      31  oil            1750, 1669, 1586, 1516,                                                   1369, 1263,                         8      81                 1212, 1183, 1140, 1025,                                                   750                                                   (neat)    __________________________________________________________________________     *.sup.1 Contains 1/2 molecules of ethyl acetate.     *.sup.2 Contains 1/2 molecules of benzene.     *.sup.3 Contains 1/3 molecules of benzene.     *.sup.4 Contains one molecule of benzene.     *.sup.5 1/2 calcium salt.monohydrate.

                                      TABLE 3    __________________________________________________________________________     ##STR26##    Com-                             Method    pound                            (Example                                          Yield                                              mp    No. R           R.sup.1     R.sup.2                                     No.) (%) (°C.)                                                        IR (KBr,    __________________________________________________________________________                                                        cm.sup.-1)    34  NH.sub.2    2-OH        5-OCH.sub.3                                     12   97  237-241 (dec.)                                                        3440, 3308, 3288,                                                        3188,                                     13   63  (CH.sub.3 COCH .sub.3H.sub.2                                                        2924, 1682, 1653,                                                        1606,                                                        1584, 1508, 1478,                                                        1443,                                                        1428, 1371, 1303,                                                        1280,                                                        1272, 1258, 1219,                                                        1201,                                                        1033, 750, 730, 554    35  NH.sub.2    4-OH        H    6    59  183-185 (dec.)                                                        3328, 3196, 1671,                                                        1636,                                     12   78  (CH.sub. 3 COCH .sub.3H.sub.2                                              O)        1608, 1375, 1249                                                        1210                                     13   65    36  NH.sub.2    2-OCOCH.sub.3                                5-OCH.sub.3                                     1    61  141-144.5 3412, 3332, 1752,                                                        1654,                                                        1604, 1585, 1492,                                                        1479,                                                        1446, 1419, 1369,                                                        1180    37  NH.sub.2    4-OCOCH.sub.3                                H    11   76  195-198 (dec.)                                                        3380, 1732, 1654,                                                        1240,                                              (EtOHH.sub.2 O)                                                        1201    38  NH.sub.2    4-OCOOCH.sub.2 CH(CH.sub.3).sub.2                                H    11   27  154-155   3428, 1752, 1661,                                                        1372,                                                        1299, 1268, 1249,                                                        1216,                                                        750    39  NH.sub.2                     ##STR27##  5-OCH.sub.3                                     15 16                                          26 80                                              187-189   3384, 3232, 3180,                                                        1685, 1663, 1499,                                                        1492, 1479, 1446,                                                        1419, 1374, 1305,                                                        1287, 1220, 1040    .sup.  40*.sup.1        NH.sub.2                     ##STR28##  H    15 16                                          82  85                                              176-179   3392, 3320, 1654,                                                        1607, 1583, 1509,                                                        1478, 1445, 1415,                                                        1369, 1299, 1280,                                                        1243, 1215, 1179,                                                        749    41  N(CH.sub.3).sub.2                    2-OH        5-OCH.sub.3                                     13   64  186-188   3188, 1637, 1583,                                                        1509,                                                        1479, 1446, 1427,                                                        1400,                                                        1375, 1324, 1262,                                                        1216,                                                        1150, 750    42  N(CH.sub.3).sub.2                    4-OH        H    13   74  210-211   3272, 2924, 2684,                                                        2608,                                              (CH.sub.3 COCH .sub.3H.sub.2                                                        2480, 2352, 2180,                                                        1636,                                                        1610, 1509, 1478,                                                        1445,                                                        1376, 1264, 1220    43         ##STR29##  4-OH        H    13   64  156-161 (dec.)                                                        3308, 1647, 1593,                                                        1513, 1474, 1433,                                                        1374, 1280, 1222,                                                        1171    44         ##STR30##  4-OH        H    13 14                                          14 69                                              199.5-202.5  (EtOHH.sub.2                                                        3344, 1651, 1635,                                                        1589, 1513, 1476,                                                        1447, 1377, 1279,                                                        1234    45         ##STR31##  4-OH        H    13   48  263-265 (dec.)                                                        3200, 1646, 1629,                                                        1585, 1474, 1467,                                                        1444,    __________________________________________________________________________                                                        1267, 1230     *.sup.1 Contains 1/4 molecules of H.sub.2 O.

                                      TABLE 4    __________________________________________________________________________     ##STR32##    Compound      Method  Yield                              mp    No.   R.sup.3              R p (Example No.)                          (%) (°C.)                                       IR (KBr, cm.sup.-1)    __________________________________________________________________________    46    H   Cl                3 17      43  116-119  3180, 1666, 1584, 1498, 1477, 1424,                                       1374, 1278, 1237, 1206, 1034, 749                                       680    47    H   Br                4 17      37  149-152 (dec.)                                       2944, 1664, 1582, 1498, 1474, 1424,                  21      31  (C.sub.6 H.sub.4n-hexane)                                       1364, 1270, 1238, 1205, 1042, 797,                                       746    48    H   Br                5 17      44  118-120  3180, 1672, 1585, 1501, 1480, 1367,                                       1241, 1211, 1040, 801, 751    49    CH.sub.3              Cl                3 17      56  97,5-100 1646, 1581, 1467, 1424, 1354, 1271,                  21      60           1234, 1203, 1147, 1044, 1019, 795,                                       750, 652    50    CH.sub.3              Br                4 17      64  103-105  1655, 1586, 1496, 1472, 144,2 1427,                                       1363, 1273, 1238, 1204, 1154, 1044,                                       1020, 804, 765    51    CH.sub.3              Br                5 17      61  92-94.5  1665, 1585, 1494, 1468, 1426, 1356,                                       1279, 1238, 1212, 1045m 1018,    __________________________________________________________________________                                       743

                  TABLE 5    ______________________________________     ##STR33##                            Meth-                            od    Com-                    (Exam-    pound                   ple   Yield mp     IR (KBr,    No.   R.sup.3 R     p   No.)  (%)   (°C.)                                               cm.sup.-1)    ______________________________________    52    H       Cl    3   17    44    175.5-178                                               3204, 3120,                            21    41    (EtOH) 2972, 1666,                                               1584, 1510,                                               1480, 1365,                                               1244, 749    53    H       Cl    6   17    45    160.5-162                                               3208, 1667,                                               1609, 1584,                                               1511, 1479,                                               1365, 1250,                                               1176, 800,                                               748    54    CH.sub.3                  Cl    3   17    40    97-99  1663, 1605,                            21    53           1581, 1509,                                               1468, 1447,                                               1351, 1278,                                               1237, 1176,                                               761    ______________________________________

                                      TABLE 6    __________________________________________________________________________     ##STR34##    Com-                        Method    pound                       (Example                                     Yield                                         mp    No. R.sup.3            R   R'            p No.) (%) (°C.)                                                   IR (KBr,    __________________________________________________________________________                                                   cm.sup.-1)    55 .sup.        H   CH.sub.3                CH.sub.3      3 18   37  136-137   1675, 1584, 1499, 1479,                                                   1466, 1353,                                19   67  (MeOH)    1286, 1240, 1208, 1058,                                                   809, 752    56 .sup.        H   CH.sub.3                 ##STR35##    3 19 20                                     69 76                                         136-137 (AcOEt)                                                   3180, 1665, 1584, 1499,                                                   1479, 1375, 1237, 1206,                                                   1047, 802, 752    57*.sup.1        H   CH.sub.3                 ##STR36##    4 19   53  amorph.   3384, 1663, 1582, 1493,                                                   1473, 1232, 1034, 751,                                                   718    58*.sup.2        H   CH.sub.3                 ##STR37##    5 19   94  146-147.5 (AcOEt)                                                   3410, 2470, 1671, 1593,                                                   1551, 1498, 1476, 1375,                                                   1351, 1239, 1204, 1036,                                                   805, 715    59*.sup.3        H   CH.sub.3                 ##STR38##    3 19 20                                     38 57                                         amorph.   3420, 1719, 1671, 1583,                                                   1501, 1474, 1235, 1025,                                                   757    60*.sup.4        H             ##STR39##        4 19 20                                     45 67                                         137-145 (dec.) (EtOHAcOEt)                                                   3400, 3170, 2640, 2500,                                                   1674, 1581, 1500, 1478,                                                   1368, 1273, 1238, 1216,                                                   1038, 976, 754, 699    61 .sup.        CH.sub.3            CH.sub.3                CH.sub.3      3 18   51   82-84    1655, 1582, 1498, 1458,                                                   1444, 1356,                                19   62  (EEt.sub.2 O)                                                   1306, 1240, 1216, 1145,                                                   1037, 809,                                20   74            741    62*.sup.1        CH.sub.3            CH.sub.3                 ##STR40##    3 19 20                                     52 77                                         116-120 (dec.) (EtOH)                                                   1653, 1465, 1353, 1272,                                                   1237, 1205, 1152, 1039,                                                   752, 704    63*.sup.1        CH.sub.3            CH.sub.3                 ##STR41##    4 19   78  150-151.5 (dec.) (EtOH)                                                   3420, 2650, 1663, 1584,                                                   1499, 1468, 1357, 1275,                                                   1238, 1208, 1037, 756    64*.sup.1        CH.sub.3            CH.sub.3                 ##STR42##    5 19   65  amorph.   3376, 2630, 1702, 1653,                                                   1581, 1455, 1203, 1033,                                                   932, 807, 750, 716    65*.sup.1        CH.sub.3             ##STR43##        4 20   62  173-175 (dec.) (EtOHH.sub.2 O)                                                   3425, 2650, 1510, 1669,                                                   1584, 1500, 1473, 1446,                                                   1354, 1277, 1238, 1217,                                                   1038, 701    66 .sup.        CH.sub.3             ##STR44##        4 19 20                                     22 41                                         135-138 (CHCl.sub.3iso-Pr.sub.2                                                   1660, 1592, 1499, 1277,                                                   1183    __________________________________________________________________________     *.sup.1 oxalic acid  salt     *.sup.2 benzoic acid  salt     *.sup.3 citric acid  salt     *.sup.4 fumaric acid  salt

                                      TABLE 7    __________________________________________________________________________     ##STR45##                                 Method    Compound                     (Example                                       Yield                                           mp    No.   R.sup.3              R       R'       p No.)  (%) (°C.)                                                   IR (KBr,    __________________________________________________________________________                                                   cm.sup.-1)    67*.sup.1          H   CH.sub.3                      CH.sub.3 3 18    45  202-206 (dec.)                                                   3420, 2660, 1670, 1578,                                                   1475, 1350,                                 19    68  (EtOH)  1243, 1229, 1173, 752,                                                   645    68 .sup.          H   CH.sub.3                       ##STR46##                               3 19    57  130-133 (EtOH)                                                   3060, 2848, 1675, 1583,                                                   1511, 1482, 1369, 1245,                                                   743    69 .sup.          H   CH.sub.3                       ##STR47##                               6 19    73  131-132.5 (AcOEt)                                                   3208, 1670, 1609, 1583,                                                   1511, 1482, 1368, 1242,                                                   1178, 799, 747    70*.sup.1          H               ##STR48##       3 20    58  181-184 (dec.) (EtOH)                                                   3044, 1675, 1605, 1581,                                                   1509, 1478, 1378, 1299,                                                   1240, 748    71*.sup.2          H               ##STR49##       3 20    41  238-241 (dec.) (EtOH)                                                   2932, 2488, 1666, 1606,                                                   1583, 1510, 1378, 1299,                                                   1240, 748    72 .sup.          CH.sub.3              CH.sub.3                      CH.sub.3 3 18    38   99.5-101                                                   1665, 1608, 1582, 1510,                                                   1474, 1353,                                 20    71  (Et.sub.2 O)                                                   1240, 1177, 1050, 765    73*.sup.1          CH.sub.3              CH.sub.3                       ##STR50##                               3 19    60  149-150.5  (EtOH)                                                   3420, 2610, 1702, 1654,                                                   1608, 1582, 1510, 1467,                                                   1356, 1247, 1175, 980,                                                   746, 643    __________________________________________________________________________     *.sup.1 fumaric acid  salt     *.sup.2 dihydrochloride-

                                      TABLE 8    __________________________________________________________________________     ##STR51##    Com-    pound                     Method  Yield                                          mp    No. R.sup.3              R.sup.8       p (Example No.)                                      (%) (°C.)                                                   IR (KBr,    __________________________________________________________________________                                                   cm.sup.-1)    74*.sup.1        H               ##STR52##    3 20      64  231-232 (dec.) (EtOH)                                                   3412, 2530, 1663, 1587,                                                   1500, 1458, 1424, 1239,                                                   1122, 747    75*.sup.2        H               ##STR53##    4 20      61  181-183 (dec.) (EtOHCH.sub.3                                                   3410, 1671, 1586, 1500,                                                   1458,1419, 1349, 1122,                                                   1034, 975, 748, 633    76*.sup.3        H               ##STR54##    3 20      58  147-148 (EtOH)                                                   3420, 2540, 1671, 1577,                                                   1499, 1477, 1357, 1235,                                                   1212, 1040, 863, 751    77*.sup.1        CH.sub.3               ##STR55##    3 20      72  210-213 (EtOH)                                                   3428, 2932, 2360, 1663,                                                   1558, 1499, 1462, 1424,                                                   1356, 1243, 1205, 1117,                                                   1029, 1005, 748    78*.sup.1        CH.sub.3               ##STR56##    4 19 20   54 84                                          195.5-197.5 (dec.) (EtOH)                                                   3404, 2928, 2380. 1645,                                                   1586, 1499, 1464, 1425,                                                   1241, 1121, 1038, 761    79*.sup.1        CH.sub.3               ##STR57##    4 20      69  210-212 (EtOHH.sub.2 O)                                                   2400, 1685, 1660, 1583,                                                   1499, 1466, 1446, 1356,                                                   1278, 1236, 1215, 1036,                                                   947, 752    __________________________________________________________________________     *.sup.1 dihydrochloride-     *.sup.2 di-fumaric acid  salt     *.sup.3 di-maleic acid  salt

                                      TABLE 9    __________________________________________________________________________     ##STR58##    Compound                  Method  Yield                                          mp    No.   R        R'       p (Example No.)                                      (%) (°C.)                                                   IR (KBr,    __________________________________________________________________________                                                   cm.sup.-1)    80    Br       Br       5 22      74  oil      1668, 1588, 1502, 1480,                                                   1449, 1379,                                                   1279, 1241, 1222, 1043,                                                   752 (neat)    81    N(CH.sub.3).sub.2                   Cl       3 17      46  oil      2940, 1663, 1585, 1500,                                                   1478, 1466,                                                   1445, 1375, 1307, 1277,                                                   1240, 1218,                                                   1042, 749 (neat)     .sup. 82*.sup.1          N(CH.sub.3).sub.2                   N(CH.sub.3).sub.2                            3 18      59  185.5-186.5 (dec.)                                                   3420, 2650, 1717, 1653,                                                   1583, 1500,                              23      57  (MeOH H.sub.2 O)                                                   1471, 1442, 1399, 1277,                                                   1213, 1156,                              24      66           1040, 717, 493                              29      87    83           ##STR59##                    ##STR60##                            3 19      38  oil      2928, 2852, 1666, 1500,                                                   1479, 1446, 1372, 1278,                                                   1240, 1219, 1045, 750     .sup. 84*.sup.2          N(CH.sub.3).sub.2                   N(CH.sub.3).sub.2                            5 20      47  amorph.  2916, 1717, 1202, 1184,                                                   1178                              24      41     .sup. 85*.sup.2           ##STR61##                    ##STR62##                            5 19      42  amorph.  2928, 1718, 1654, 1442,                                                   1375, 1231, 1206    __________________________________________________________________________     *.sup.1 di-oxalic acid  salt     *.sup.2 di-citric acid  salt

                                      TABLE 10    __________________________________________________________________________     ##STR63##    Compound              Method  Yield                                      mp    No.   R      R'     p (Example No.)                                  (%) (°C.)                                           IR (KBr, cm.sup.-1)    __________________________________________________________________________    86    Cl     Cl     3    22    79 93-96                                           2920, 1663, 1610, 1510, 1477,                                           1437,                                           1375, 1249, 1180, 790, 757    87    Cl     Cl     6    22    70 oil  1664, 1610, 1584, 1510, 1376,                                           1356,                                           1303, 1249, 1175, 751, 645 (neat)    88    N(CH.sub.3).sub.2                 Cl     3    21    50 oil  2936, 1660, 1608, 1583, 1510,                                           1477,                                           1445, 1375, 1301, 1277, 1246,                                           1176,                                           749 (neat)    .sup. N(CH.sub.3).sub.2                 N(CH.sub.3 ).sub.2                        3    18    55 amorph.                                           1718,1653, 1604, 1577, 1509,                                           1473,                             23    49      1437, 1375, 1300, 1225, 1174                             24    63    .sup.  90*.sup.1           ##STR64##                  ##STR65##                        3    20    56 amorph.                                           2928, 1722, 1655, 1604, 1577,                                           1509, 1473, 1442, 1374, 1300,                                           1236    .sup.  91*.sup.2           ##STR66##                  ##STR67##                        6    19 20 37 59                                      amorph.                                           2924, 2856, 1701, 1685, 1654,                                           1374, 1239, 1172, 979, 747,    __________________________________________________________________________                                           643     *.sup.1 di-citric acid  salt     *.sup.2 fumaric acid  salt

                                      TABLE 11    __________________________________________________________________________     ##STR68##    Compound       Method  Yield                               mp    No.   R      p (Example No.)                           (%) (°C.)                                      IR KBr, cm.sup.-1)    __________________________________________________________________________    92    Cl     3 21      82  158-162                                      1650, 1585m 1499m 1479, 1446, 1419,                                      1374, 1300, 1284, 1264, 1241m 1219,                                      1038, 750    93    N(CH.sub.3).sub.2                 3 18      61  159-162                                      3416, 3320, 2932, 1684, 1647, 1584,                   20      75  (CH.sub.3 COCH.sub.3)                                      1499, 1478, 1465, 1447, 1419, 1375,                   25      80         1300, 1283, 1264, 1241, 1220, 750     94*           ##STR69##                 3 19 25   48 74                               62-66 (dec.)  (CH.sub.3 COCH.sub.3)                                      3324, 3180, 2916, 2848, 1657, 1584,                                      1498, 1478, 1445, 1418, 1372, 1299,                                      1285, 1264, 1239, 1218,    __________________________________________________________________________                                      1038     *Contains 2 molecules of acetone.

                                      TABLE 12    __________________________________________________________________________     ##STR70##    Com-                            Method    pound                           (Example                                         Yield                                             mp    No. R          R'             p No.) (%) (°C.)                                                        IR (KBR,    __________________________________________________________________________                                                        cm.sup.-1)    95  NH.sub.2   Cl             3 21   46  200-204    3392, 1657, 1617,                                                        1608,                                                        1577, 1477, 1368,                                                        1302,                                                        1247, 1208, 748    96  NH.sub.2   N(CH.sub.3).sub.2                                  3 20   49  134-136    3384, 3324, 3180,                                                        2932,                                    25   48  (CH.sub.3 COCH.sub.3H.sub.2                                                        1657, 1607, 1582,                                                        1509,                                                        1477, 1444, 1419,                                                        1370,                                                        1299, 1280, 1244,                                                        1212,                                                        1175, 748    97  NH.sub.2                    ##STR71##     3 20 25                                         66 62                                             143-146 (dec.) (CH.sub.3                                             COCH.sub.3)                                                        3384, 3320, 2920,                                                        2848, 1655, 1608,                                                        1583, 1509, 1478,                                                        1445, 1419, 1370,                                                        1299, 1281, 1245,                                                        1215, 1175    98  N(CH.sub.3).sub.2                   Cl             3 21   64  118-121    1654, 1607, 1582,                                                        1509,                                                        1478, 1445, 1420,                                                        1396,                                                        1376, 1320, 1242,                                                        1177,                                                        1146, 762, 748    .sup.  99*.sup.1        N(CH.sub.3).sub.2                   N(CH.sub.3).sub.2                                  3 18   37  168-169.5  3412, 1648, 1602,                                                        1577,                                    25   50  (CH.sub.3 COCH .sub.3MeOH)                                                        1478, 1379, 1363,                                                        1237,                                                        1178, 984    100 N(CH.sub.3).sub.2                    ##STR72##     3 20   35  148-151.5 (dec.) (EtOH)                                                        2920, 2796, 1654,                                                        1606, 1578, 1509,                                                        1478, 1446, 1375,                                                        1316, 1285, 1243,                                                        1170    101         ##STR73## Cl             3 21   74  amorph.    1654, 1607, 1509,                                                        1477, 1445, 1376,                                                        1235, 1175, 1110,                                                        1030, 749    .sup. 102*.sup.2         ##STR74## N(CH.sub.3).sub.2                                  3 18 25                                         29 51                                             188-200.5 (dec.) (EtOHH.sub.2                                                        3400, 1647, 1607,                                                        1577, 1510, 1473,                                                        1446, 1377, 1235    103         ##STR75## Cl             3 21   88   94-96     1655, 1608, 1509,                                                        1473, 1465, 1458,                                                        1430, 1376, 1283,                                                        1227, 1174, 1026    104         ##STR76##                    ##STR77##     3 20 26                                         31 66                                             amorph.    1658, 1594, 1509,                                                        1444, 1428,    __________________________________________________________________________                                                        1225     *.sup.1 maleic acid  salt     *.sup.2 fumaric acid  salt

                                      TABLE 13    __________________________________________________________________________     ##STR78##    Com-                       Method    pound                      (Example                                    Yield                                        mp    No. R.sup.3  R      R'     No.) (%) (°C.)                                                   IR (KBr,    __________________________________________________________________________                                                   cm.sup.-1)    105 H        H      C(CH.sub.3).sub.3                               27   93  182-183    3400, 3256, 1669, 1584,                                                   1500, 1479,                                        (EtOHCH.sub.2 Cl.sub.2)                                                   1359, 1238, 1213, 1041,                                                   745      .sup. 106*.sup.1        CH.sub.3 H      C(CH.sub.3).sub.3                               27   84  187-188    3364, 1664, 1560, 1499,                                                   1380, 1353,                                        (EtOHH.sub.2 O)                                                   1281, 1240, 1213, 1128,                                                   1041, 748     .sup. 107*.sup.2        CH.sub.3                  ##STR79##    27 28                                    28 84                                        145-146 (dec.) (EtOHH.sub.2 O)                                                   3380, 2430, 1691, 1653,                                                   1617, 1576, 1493, 1355,                                                   1235, 1212, 1037, 864 750    108 CH.sub.2 CONH.sub.2                 H      C(CH.sub.3).sub.3                               27   68  202-204 (dec.)                                                   3332, 3172, 2944, 1658,                                                   1585, 1499,                                        (CH.sub.3 COCH.sub.3H.sub.2 O)                                                   1478, 1458, 1446, 1418,                                                   1399, 1365,                                                   1302, 1282, 1264, 1241,                                                   1220, 1034, 747     .sup. 109*.sup.3        (CH.sub.2).sub.3 N(CH.sub.3).sub.2                 H      C(CH.sub.3).sub.3                               27   48  amorph.    3368, 2936, 1700, 1637,                                                   1602, 1578,                                                   1437, 1375, 1315, 1309,                                                   1232    110 CH.sub.2 CONH.sub.2                 H      C(CH.sub.3).sub.3                               27   82  amorph.    3320, 3212, 3184, 3060,                                                   2592, 1661,                                                   1657, 1607, 1583, 1509,                                                   1478, 1446,                                                   1369, 1299, 1244,    __________________________________________________________________________                                                   1215     *.sup.1 1/2-succinic acid  salt     *.sup.2 di-maleic acid  salt     *.sup.3 di-citric acid  salt, contains 1 molecules of ethyl acetate

Pharmacological Activities

Calcium antagonists have not only potentially beneficial effects in thetreatment of many diseases but also serve as valuable research tools toelucidate excitation-contraction coupling in various muscle types (A.Fleckenstein, Ann. Rev. Pharmacol., 17, 149-166, 1977). Therefore, weexamined the calcium-antagonistic activity of the compounds of thisinvention.

Pharmacological test I

The action potentials on the smooth muscles of uterus, teania coli andportal vein are dependent on calcium ion, and therefor these smoothmuscle preparations are useful for screening of calcium antagonists. Wemeasured the calcium-antagonistic activity of the compounds by themethod using guinea-pig teania coli preparation.

Isolated guinea-pig teania coli was suspended in a 20 ml organ bath withKrebs solution at 32° C. and bubbled with 5% carbon dioxide in oxygen.After equilibration, the muscle was washed with Ca⁺⁺ -free Krebssolution, and when the muscle had relaxed to basal level, it wassuspended in Ca⁺⁺ -free-high-K Krebs solution.

The muscle was exposed to test compounds for 5 minutes before additionof CaCl₂, and the contraction evoked by CaCl₂ (3×10⁻⁴ M) was recordedisotonically. The calcium-antagonistic activity was represented by theconcentration of test compound which elicited 50% inhibition of Ca⁺⁺-evoked contraction (IC₅₀).

As shown in Table 14, the compounds of this invention hadcalcium-antagonistic activity.

Blood platelet plays an important role not only in hemostasis but alsoin thrombosis. Platelet hyperaggregability leads to an increase in thenumber of circulating platelet aggregates, which may contribute towardthe development of cardiac arrythmias, cardiac arrest or myocardialinfarction. These cardiovascular diseases can be prevented by inhibitionof platelet aggregation. Therefore, we screened the influence of testcompounds on platelet aggragation in vitro, and found that they haveanti-aggregatory activity.

Pharmacological test II

Blood was obtained from an anesthetized rabbit using 0.1 volumes of 3.8%sodium citrate as anticoagulant. Platelet rich plasma(PRP) was isolatedby centrifugation at 650 rpm for 10 minutes at room temperature. Afterpreincubation of PRP (0.25 ml) with various concentrations of testcompounds (14 μl) for 1 minute at 37° C., collagen (3 μg/ml:finalconcentration) or ADP (3 μM:final concentration) was added to induceaggregation and the aggregation profiles were monitored with RIKADENKIsix-channel aggregometer. The control experiment contained salineinstead of test compound.

The anti-aggregatory activity was represented by the concentration oftest compound which elicited 50% inhibition of control response.

As shown in the Table 15, the compounds of this invention hadanti-aggregatory activity.

                  TABLE 14    ______________________________________    Calcium-antagonistic activity    Compound No.    IC.sub.50 [M]    ______________________________________    58              2.6 × 10.sup.-6    59              2.0 × 10.sup.-6    61              2.5 × 10.sup.-6    62              1.6 × 10.sup.-6    64              3.0 × 10.sup.-6    65              1.8 × 10.sup.-6    68              1.9 × 10.sup.-6    71              2.0 × 10.sup.-6    72              2.6 × 10.sup.-6    73              3.4 × 10.sup.-6    75              3.0 × 10.sup.-6    77              1.6 × 10.sup.-6    79              3.9 × 10.sup.-6    107             3.8 × 10.sup.-6    ______________________________________

                  TABLE 15    ______________________________________    Anti-aggregatory activity    Compound No.    IC.sub.50 [M]    ______________________________________    55              3.2 × 10.sup.-6    57              3.2 × 10.sup.-6    63              3.2 × 10.sup.-6    67              1.6 × 10.sup.-6    76              3.2 × 10.sup.-6    78              3.5 × 10.sup.-6    82              3.2 × 10.sup.-6    105             1.0 × 10.sup.-6    106             1.3 × 10.sup.-6    ______________________________________

Toxicity test

Acute toxicity of the compounds of this invention is shown in Table 16.(animal)

Male ddy-SLC strain mice (4 weeks of age, weighing 19-21 g) were placedin a breeding room of constant temperature and huminity (23±1° C.,55±5%) and fed freely pellet diet and water ad. libitum for a week. Miceshowing normal growth were selected for the test. (method ofadministration)

Test compounds are suspended in 0.5% tragacanth suspention andadministered orally in a dose of 0.5 ml/20 g body weight.

                  TABLE 16    ______________________________________    Compound No.   LD.sub.50 (mg/Kg)    ______________________________________    73             500-1000    77             >1280    ______________________________________

The compounds can be administered either orally or parenterally. Thedosage forms are tablet, capsule, granule, powder, suppository,injection, etc. The dose is adjusted depending on symptom, dosage form,etc., but usual daily dosage is 1 to 5,000 mg, preferably 10 to 1,000mg, in one or a few divided doses.

Examples of formulation are shown below.

    ______________________________________    Example of formulation    (a) tablet    ______________________________________    compound No. 55          30     mg    lactose                  150    mg    crystalline cellulose    50     mg    calcium carboxymethylcellulose                             7      mg    magnesium stearate       3      mg    total                    240    mg    compound No. 62          50     mg    lactose                  120    mg    crystalline cellulose    60     mg    calcium carboxymethylcellulose                             7      mg    magnesium stearate       3      mg    total                    240    mg    compound No. 65          60     mg    lactose                  120    mg    crystalline cellulose    60     mg    calcium carboxymethylcellulose                             7      mg    magnesium stearate       3      mg    total                    250    mg    compound No. 67          40     mg    lactose                  150    mg    crystalline cellulose    50     mg    calcium carboxymethylcellulose                             7      mg    magnesium stearate       3      mg    total                    250    mg    compound No. 68          70     mg    lactose                  110    mg    crystalline cellulose    60     mg    calcium carboxymethylcellulose                             7      mg    magnesium stearate       3      mg    total                    250    mg    ______________________________________

The tablets may be treated with the common film-coating and further withsugar-coating.

    ______________________________________    (b)    granule           compound No. 73       30     mg           polyvinylpyrrolidone  25     mg           lactose               385    mg           hydroxypropylcellulose                                 50     mg           talc                  10     mg           total                 500    mg           compound No. 77       50     mg           polyvinylpyrrolidone  25     mg           lactose               365    mg           hydroxypropylcellulose                                 50     mg           talc                  10     mg           total                 500    mg    (c)    powder           compound No. 82       30     mg           lactose               500    mg           starch                440    mg           colloidal silica      30     mg           total                 1000   mg           compound No. 105      50     mg           lactose               480    mg           starch                440    mg           colloidal silica      30     mg           total                 1000   mg    (d)    capsule           compound No. 106      30     mg           lactose               102    mg           crystalline cellulose 56     mg           colloidal silica      2      mg           total                 190    mg           compound No. 107      50     mg           glycerol              329.8  mg           butyl p-hydroxybenzoate                                 0.02   mg           total                 380    mg    ______________________________________

What we claim is:
 1. A compound of the formula or a salt thereof,##STR80## wherein R¹ is ##STR81## R² is selected from the groupconsisting of hydrogen, (C₁ -C₆)alkyl, halogen, nitro, hydroxy, amino,(C₁ -C₆)alkoxy, (C₁ -C₆)alkanoyloxy, (C₁ -C₆)alkylamino and (C₁-C₆)alkoxycarbonyloxy;R³ is hydrogen, (C₁ -C₆)alkyl or ##STR82## R⁴ andR⁵ are same or different and are selected from the group consisting ofhydroxy, halogen, methoxy ##STR83## R⁶ and R⁷ are same or different andare selected from the group consisting of hydrogen, (C₁ -C₆)alkyl, (C₄-C₇)cycloalkyl and phenyl-(C₁ -C₆)alkyl, and said phenyl nucleus can besubstituted by hydroxy, (C₁ -C₆)alkyl or (C₁ -C₆)alkoxy; R⁸ is selectedfrom the group consisting of hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkanoyl,(C₁ -C₆)alkoxycarbonyl, carboxy, phenyl, phenylcarbonyl, phenyl-(C₁-C₆)alkyl, phenyl-(C₁ -C₆)alkanoyl, and phenylcarbonyl-(C₁ -C₆)alkyl,and said alkyl and alkanoyl groups can be substituted by hydroxy, (C₁-C₆)alkoxy, carboxy, (C₁ -C₆)alkoxycarbonyl, halogen, amino, (C₁-C₆)alkylamino or tetrahydropyranyloxy, and said phenyl nucleus can besubstituted by (C₁ -C₆)alkyl, hydroxy, (C₁ -C₆)alkoxy, (C₁ -C₆)alkanoyl,(C₁ -C₆)alkoxycarbonyl, halogen, amino or (C₁ -C₆)alkylamino; A, B and Zare same or different and are (C₁ -C₆)alkylene; and m and n each is 0or
 1. 2. The compound as in claim 1, wherein m is
 1. 3. The compound asin claim 1, wherein m is
 0. 4. The compound as in claim 1, wherein R¹ ishydroxy, methoxy, acetyloxy, tetrahydropyranyloxy,isobutyloxycarbonyloxy or dimethylamino.
 5. The compound as in claim 1,wherein R² is hydrogen, methyl, methoxy, hydroxy, chloro or nitro. 6.The compound as in claim 1, wherein R³ is hydrogen or methyl.
 7. Thecompound as in claim 1, wherein R⁴ is chloro or bromo.
 8. The compoundas in claim 1, wherein R³ is ##STR84## and R⁵ is chloro, bromo, hydroxy,methoxy, amino or dimethylamino.
 9. The compound as in claim 1, whereinat least one of R⁴ and R⁵ is ##STR85## and R⁶ and R⁷ each is hydrogen,methyl, cyclohexyl, tert-butyl or 3,4-dimethoxyphenethyl.
 10. Thecompound as in claim 1, wherein at least one of R⁴ and R⁵ is ##STR86##and R⁸ is ethoxycarbonyl, hydroxyethyl, benzoyl, benzyl,4-fluorobenzoyl, benzoylmethyl, 3,4-dimethoxyphenethyl or3,4,5-trimethoxyphenethyl.
 11. The compound as in claim 1, wherein R⁴ isselected from the group consisting of hydrogen, halogen, ##STR87## 12.The compound as in claim 1, wherein all halogens specified therein areselected from the group consisting of chloro, bromo and fluoro.
 13. Thecompound as in claim 2, wherein A and B are --CH₂ --.
 14. A compound ofthe formula [I] or a salt thereof, ##STR88## wherein R¹ is ##STR89## R²is hydrogen or methoxy; R³ is hydrogen or methyl;R⁴ is selected from thegroup consisting of chlorine, bromine, ##STR90## and piperidine whichcan be substituted by benzyl, phenylcarbonyl or (fluorophenyl)carbonyl;R⁶ and R⁷ are same or different and are selected from the groupconsisting of hydrogen, methyl, cyclohexyl and phenethyl which can besubstituted by one or more methoxy group(s); R⁸ is phenethyl which canbe substituted by one or more methoxy group(s) or phenylcarbonylmethyl;A and B are same or different and are (C₁ -C₆)alkylene; and m is
 0. 15.3,4-Dihydro-2-[2-(3-dimethylaminopropoxy)-5-methoxyphenyl]-3-oxo-2H-1,4-benzothiazineas in claim
 14. 16.3,4-Dihydro-2-[5-methoxy-2-[3-(N-methylcyclohexylamino)propoxy]-4-methyl-3-oxo-2H-1,4-benzothiazineas in claim
 14. 17.3,4-Dihydro-2-[5-methoxy-2-[4-(N-methylcyclohexylamino)butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazineas in claim
 14. 18.2-[2-[4-(4-Benzoylpiperidino)butoxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazineas in claim
 14. 19.3,4-Dihydro-2-[4-(3-dimethylaminopropoxy)phenyl)-3-oxo-2H-1,4-benzothiazineas in claim 14.20.3,4-Dihydro-2-[4-[3-(N-methylcyclohexylamino)propoxy]phenyl]-3-oxo-2H-1,4-benzothiazineas in claim
 14. 21.3,4-Dihydro-2-[5-methoxy-2-[4-[4-(3,4,5-trimethoxyphenethyl)piperazino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazineas in claim
 14. 22. A compound of the formula [I] or a salt thereof,##STR91## wherein R¹ is ##STR92## R² is hydrogen or methoxy; R³ is##STR93## R⁴ is chlorine, bromine, ##STR94## R⁵ is chlorine, bromine,hydroxy, ##STR95## R⁶ and R⁷ are same or different and are hydrogen,methyl or cyclohexyl;R⁸ is phenylcarbonylmethyl or ethoxycarbonyl; A andB are same or different and are (C₁ -C₆)alkylene; Z is (C₁ -C₆)alkylene;m is 0; and n is 0 or
 1. 23.3,4-Dihydro-2-[2-(3-dimethylaminopropoxy)-5-methoxyphenyl]-4-(3-dimethylaminopropyl)-3-oxo-2H-1,4-benzothiazineas in claim
 22. 24. A compound of the formula [I] or a salt thereof,##STR96## wherein R¹ is ##STR97## R² is hydrogen or methoxy; R³ ishydrogen, methyl or ##STR98## R⁴ is ##STR99## R⁵ is hydroxy, amino ordimethylamino; R⁶ and R⁷ are same or different and are hydrogen or--C(CH₃)₃ --;Z is (C₁ -C₃)alkylene; m is 1; and n is 0 or
 1. 25.2-[2-(3-tert-Butylamino-2-hydroxypropoxy)-5-methoxyphenyl]-3,4-dihydro-3-oxo-2H-1,4-benzothiazineas in claim
 24. 26.3,4-Dihydro-2-[2-[2-hydroxy-3-(4-phenacylpiperazino)propoxy]-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazineas in claim
 24. 27. A compound of the formula [I] or a salt thereof,##STR100## wherein R¹ is selected from the group consisting of hydrogen,hydroxy, (C₁ -C₆)alkoxy, (C₁ -C₆)alkanoyloxy, (C₁ -C₆)alkoxycarbonyloxy,tetrahydropyranyloxy, amino, and (C₁ -C₆)alkylamino;R² is selected fromthe group consisting of hydrogen, (C₁ -C₆)alkyl, nitro, hydroxy, amino,(C₁ -C₆)alkoxy, (C₁ -C₆)alkanoyloxy, (C₁ -C₆)alkylamino and (C₁ -C₆)alkoxycarbonyloxy; R³ is (C₁ -C₆)alkyl or ##STR101## R⁵ is selected fromthe group consisting of hydroxy, halogen, methoxy, ##STR102## R⁶ and R⁷are same or different and are selected from the group consisting ofhydrogen, (C₁ -C₆)alkyl, (C₄ -C₇)cycloalkyl and phenyl-(C₁ -C₆)alkyl,and said phenyl nucleus can be substituted by hydroxy, (C₁ -C₆)alkyl or(C₁ -C₆)alkoxy; R⁸ is selected from the group consisting of hydrogen,(C₁ -C₆)alkyl, (C₁ -C₆)alkanoyl, (C₁ -C₆)alkoxycarbonyl, carboxy,phenyl, phenylcarbonyl, phenyl-(C₁ -C₆)alkyl, phenyl-(C₁ -C₆)alkanoyl,and phenylcarbonyl-(C₁ -C₆)alkyl, and said alkyl and alkanoyl groups canbe substituted by hydroxy, (C₁ -C₆)alkoxy, carboxy, (C₁-C₆)alkoxycarbonyl, halogen, amino, (C₁ -C₆)alkylamino ortetrahydropyranyloxy, and said phenyl nucleus can be substituted by (C₁-C₆)alkyl, hydroxy, (C₁ -C₆)alkoxy, (C₁ -C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, halogen, amino or (C₁ -C₆)alkylamino; A, B and Z aresame or different and are (C₁ -C₆)alkylene; and n is 0 or
 1. 28. Apharmaceutical composition having a platelet anti-aggregation effectcomprising (i) a pharmaceutical carrier and (ii) a plateletanti-aggregative effective amount of a compound of claim
 1. 29. A methodof preventing the aggregation of platelets comprising administering thecomposition of claim 28 in a platelet anti-aggregative effective amount.30. A pharmaceutical composition having a platelet anti-aggregationeffect comprising (i) a pharmaceutical carrier and (ii) a plateletanti-aggregative effective amount of a compound of claim
 27. 31. Amethod of preventing the aggregation of platelets comprisingadministering the composition of claim 30 in a platelet anti-aggregativeeffective amount.
 32. A method of lowering excessive calcium bloodlevels comprising administering a compound of claim 1 in an amountsufficient to lower excessive calcium blood levels.